Celiac disease is a common inflammatory intestinal disease induced by dietary gluten in genetically predisposed individuals. While the presence of HLA-DQ2 or DQ8-restricted gliadin-specific CD4 T cells is an essential component of the disease in the gut lamina propria, convergent observations indicate that stress of the epithelium lining the gut leads to the induction of MHC class-1 like ligands which in turn expand and activate intraepithelial lymphocytes (IEL) with cytolytic activity. Activated lELs not only contribute to the destruction of the epithelium, but they undergo transformation into lymphomas whh increased frequency. This proposal will explore at the cellular and molecular level the interactions between the diseased celiac epithelium and lELs. Specifically, studies will focus on the epithelial induction of HLA-E and MIC and their interaction with their cognate NKG2 receptors expressed by lELs. Specific aim 1 will use spectratyping and sequencing to perform high resolution analysis of the clonal composition of the IEL T cell receptor repertoire at different stages of the disease and in normal controls. Specific aim 2 will determine the regulation of expression and function of the NKG2 receptors that recognize HLA-E and MIC on celiac lELs. Specific aim 3 will further dissect the molecular and biochemical basis of NKG2 receptor signaling in celiac lELs. Specific aim 4 will study the expression of HLA-E and MIC by celiac intestinal epithelial cells and their induction by gliadin and stress in vivo and in organ culture. Collectively, these studies will dissect the fine regulation of human effector CTLs in a diseased intestinal epithelium by a novel ligand/receptor system linking innate and adaptive immunity.